Managing Fragile X Syndrome. Despite increasing knowledge of the molecular underpinnings of fragile X, current treatment of the disorder remains symptomatic. ADHD and ADHD-like symptoms are typically well controlled by stimulants, including methylphenidate and Adderall, and α2-agonists, such as clonidine (Xxxxxxxx et al. 1988; Xxxxx-Xxxxxx and Potanos 2004). Selective serotonin reuptake inhibitors (SSRIs) are commonly used to counter perseverative behaviors, compulsions, and social anxiety. Antipsychotics, such as risperidone and aripiprazole, are well tolerated and can be useful for the reduction of aggression, irritability, and other aberrant social behaviors. Fragile X patients with seizures are treated with various anticonvulsants, including valproic acid, carbamazepine, and gabapentin (Xxxxx-Xxxxxx and Potanos 2004). While current therapies are limited to the reduction of symptoms, several drugs are under development for the treatment of the underlying defect in fragile X syndrome, excessive mGluR5 signaling. FMRP, the protein encoded by FMR1, represses the postsynaptic translation of mRNAs essential for the process known as mGluR-LTD, or long-term depression triggered by metabotropic glutamate receptors. In mGluR-LTD, the activation of mGluR5 leads to increased protein translation in the synapse. An ensuing cascade of events results in the internalization of AMPA and NMDA receptors and an overall reduction in strength or elimination of the synaptic connection. In the functional absence of FMRP, as is seen in fragile X syndrome, there is a lack of repression of the mGluR5-dependent synaptic protein translation, leading to increased LTD, increased synapse loss, and decreased intellectual function (Bear et al. 2004). Hypothesizing that they could reduce this excessive LTD, positive modulators of AMPA-Rs and several selective antagonists of mGluR5 have entered clinical trials (Xxxxx-Xxxxxx et al. 2006; Xxxxx-Xxxxxx et al. 2009; Xxxxxxxx et al. 2009). While preliminary results on the ampakine CX516 did not reveal any significant cognitive or behavioral improvements from this class of drug (Xxxxx-Xxxxxx et al. 2006), work in fragile X animal models has shown strong benefits from mGluR5 blockade, giving much optimism for the success of this novel therapeutic strategy (XxXxxxx et al. 2005; Yan et al. 2005; Xxxxxx et al. 2006). In addition to currently employed and investigational pharmacologic therapies, fragile X syndrome is also managed through educational and behavioral interventions...
